1. Field of the Invention
The present invention relates to a patient-monitoring system that processes information from one or more blood tests, e.g. a blood test that measures the Apo E genotype.
2. Description of the Related Art
Although mortality rates for cardiovascular disease (CVD) have been declining in recent years, this condition remains the primary cause of death and disability in the United States for both men and women. In total, more than 60 million Americans have a form of CVD, which includes high blood pressure (approximately 50 million Americans), coronary heart disease (12.5 million), myocardial infarction (7.3 million), angina pectoris (6.4 million), stroke (4.5 million), congenital cardiovascular defects (1 million), and congestive heart failure (4.7 million). Atherosclerotic cardiovascular disease (ASCVD), a form of CVD, can cause hardening and narrowing of the arteries, which in turn restricts blood flow and impedes delivery of vital oxygen and nutrients to the heart. Progressive atherosclerosis can lead to coronary artery, cerebral vascular, and peripheral vascular disease which in combination result in approximately 75% of all deaths attributed to CVD.
Various lipoprotein abnormalities, including elevated concentrations of low-density lipoprotein cholesterol (LDL cholesterol), increased small dense LDL cholesterol subfractions and others, are causally related to the onset of ASCVD because over time these compounds contribute to a harmful formation and build up of atherosclerotic plaque in an artery's inner walls, thereby restricting blood flow. The likelihood that a patient will develop ASCVD generally increases with increased levels of LDL cholesterol, which is often referred to as ‘bad cholesterol’. Conversely, high-density lipoprotein cholesterol (HDL cholesterol) can function as a ‘cholesterol scavenger’ that binds LDL cholesterol and transports it back to the liver for re-circulation or disposal. This process is called ‘reverse cholesterol transport’. A high level of HDL cholesterol is therefore associated with a lower risk of developing heart disease and stroke, and thus HDL cholesterol is typically referred to as ‘good cholesterol’.
Apolipoprotein E (Apo E) plays an important role in lipoprotein metabolism, functioning as a ligand for lipoprotein receptors. It is one of the most common genes affecting LDL cholesterol levels and is linked to CVD, heart disease, type II Alzheimer's disease, and hypercholesterolemia type III. Different Apo E isoforms alter plasma lipoprotein concentrations having different receptor affinities. This is often phenotypically expressed in combination with varying environmental stimuli or genetic associations. The human Apo E gene has three common alleles (e2, e3, e4) coding for the Apo E protein as three isoforms (E2, E3, E4), which vary in the amino acids present at positions 112 and 158 of the protein. There are three homozygous (e4/e4, e3/e3, and e2/e2) and three heterozygous (e4/e3, e4/e2, and e3/e2) genotypes and phenotypes resulting from simple co-dominant Mendelian inheritance of the Apo E gene. The Apo E genotypes include Apo E2 (e2/e2, e2/e3), Apo E3 (e3/e3, e2/e4), and Apo E4 (e3/e4, e4/e4). Isoforms of the Apo E protein are created primarily in the liver and brain, and transport lipids to help clear dietary fats, such as triglycerides, from the blood.
Mechanistically, Apo E2 is associated with a slow conversion of intermediate density lipoprotein cholesterol (IDL cholesterol) to LDL cholesterol, leading to a decrease in plasma cholesterol and increased triglycerides. Apo E3 has normal lipid metabolism, thus no genotype impact. Apo E4 is associated with an inhibition of the normal cholesterol clearing process, which implies a limitation of HDL cholesterol binding leading to an increase in LDL cholesterol and triglycerides.
Recent studies indicate that patients with the genotype of at least one Apo E e4 allele (e4/4 and e4/3; 25% of population) have the highest for CVD and are associated with various clinical atherosclerotic syndromes. The Apo E e4 allele is therefore a ‘genetic marker’ for these conditions. However, genetic and environmental stress factors must contribute to the phenotypic expression of associated heart disease. For example, patients with the Apo E e4 allele have a predisposition to elevated cholesterol and increased cardiac risk when their diet is high in saturated fats and/or alcohol. Environmental factors, such as diet and exercise, may therefore dictate whether or not a patient actually develops these harmful conditions.
Patients with the late onset of type II Alzheimer's disease, which typically develops after age 65, have also been linked to the Apo E e4 genotype. The risk of developing this condition is increased in a patient homozygous for e4 (i.e., e4/e4) compared to a heterozygous patient (i.e., e2/e4 or e3/e4). About 35 to 50% of all patients with late-onset Alzheimer's express this gene.
Patients with the Apo E2 genotype (about 10% of the population) typically have a slower conversion metabolism, leading to a decrease in plasma cholesterol and increased triglycerides. Studies show that patients with an Apo E e2/e2 combination (less than 1% of the population) have a predisposition to Type III Hyperlipidemia, which may account for as much as 5% of all cases of early coronary heart disease (CHD). This means that patients with this marker are genetically predisposed to increased CVD risk.
A blood test, called Apo E genotype, can identify a given patient's isoform variation (genotype). This blood test can be coupled with blood tests for various other cardiac risk markers, including a lipoprotein analysis (also called a lipoprotein profile or lipid panel) that measures, among other compounds, blood levels of total cholesterol, LDL cholesterol, and HDL cholesterol. One method for measuring HDL and LDL cholesterol is described in U.S. Pat. No. 6,812,033, entitled ‘Method for identifying risk cardiovascular disease patients’. This patent, assigned to Berkeley HeartLab Inc. and incorporated herein by reference, describes a blood test based on a gradient-gel electrophoresis (GGE). Gradient gels used in GGE are typically prepared with varying concentrations of acrylamide and can separate macromolecules with relatively high resolution compared to conventional electrophoretic gels. Sub-classes of both HDL and LDL cholesterol can be determined by GGE. For example, GGE can differentiate up to seven subclasses of LDL cholesterol (classified as LDL I, IIa, IIb, IIIa, IIIb, IVa, and IVb), and up to five subclasses of HDL (classified as HDL 2b, 2a, 3a, 3b, 3c). These tests correlate to a technique called analytic ultracentrifugation (AnUC), which is an established clinical research standard for lipoprotein subfractionation.
GGE can differentiate the most atherogenic particles, LDL IIIa, IIIb, and IVb, and also the most helpful HDL particle, HDL 2b. Elevated levels of LDL IVb, which represents the smallest LDL cholesterol particles, have been reported to have an independent association with arteriographic progression; a combined distribution of LDL IIIa and LDL IIIb typically reflects the severity of this trait. High levels of HDL 2b increase the efficacy of reverse cholesterol transport; while low levels of HDL 2b, indicating less efficient reverse cholesterol transport, can increase the risk of CVD and atherosclerosis.